Project Summary/Abstract Salivary gland dysfunction occurs as a result of pathological injury after radiotherapy for head and neck cancer as well as due to the autoimmune disease Sjogren?s Syndrome and severely impairs the oral health and quality of life of patients. Current treatment options focus on short-term relief from the symptoms but there are no long-term restorative therapies available. Potential regenerative strategies for restoring saliva production include synthesizing artificial salivary glands from stem cells or repopulating the saliva-producing acinar cells that are preferentially damaged by these pathologies. However, the mechanisms that regulate the formation and replacement of acinar cells are not known. In this application I propose to define the mechanisms that control the generation of secretory acini using the developing salivary gland. Acinar cells develop from SOX10+ progenitors through a series of stages marked by proliferation, differentiation, maturation and polarization. My preliminary data suggests that the tyrosine kinase growth factor receptor, ERBB3, is necessary and sufficient for the generation of acini, but whether ERBB3 signaling regulates each stage of acinar cell development is unclear. Thus, here I will test the hypothesis that ERBB3 and its ligand neuregulin 1 (NRG1) regulate multiple stages of acinar cell development. This proposal will address my hypothesis via 3 specific aims: 1) Define the requirement of NRG1/ERBB3 signaling in the different stages of acinus formation, 2) Determine the contribution of neuronal vs. mesenchymal NRG1 to acinar cell development and 3) Identify the signaling pathways downstream of NRG1/ERBB3 that regulate acinar morphogenesis. These aims will be achieved using a combination of biochemical, immunochemical, genetic, and high resolution imaging techniques. Outcomes from this investigation will be utilized in the development of artificial SGs as well as in regenerative studies with the long-term aim of developing therapeutic applications for reversing salivary function.